Colorectal cancer (CRC) is the second leading cause of cancer deaths among Americans. With proper screening and removal of adenomatous polyps, CRC risk reduction has been very promising. However, only ~50% of the at-risk population (age >50) receives any sort of screening and many undergo tests with suboptimal sensitivity. This underscores the need for developing alternate cancer prevention strategies such as chemoprevention. Of the myriad of purported agents, nonsteroidal anti-inflammatory drugs (NSAIDS) have reliably shown a positive outcome. Indeed, epidemiological, experimental and clinical trials unequivocally point to the CRC preventive benefits of NSAIDS. However, the efficacy is relatively modest (30-50% risk reduction) and requires more than a decade to show significant benefits. In addition, the use of NSAIDS has been shown linked to severe side-effects including ulcers, GI bleeding, hemorrhagic strokes etc, thereby cautioning that the risks may outweigh the benefits of aspirin and NSAIDS in preventing CRC for average risk use. To improve the risk-benefit analysis, it is therefore critical to selectively target subjects that can efficiently respond to chemopreventive efficacy of NSAIDS and at the same time leave out the population least likely to benefit. It is conceivable that responsive patients could be targeted with lower efficacious doses to avoid associated toxicity. Gender is an important risk factor for CRC with women frequently having biological differences (higher prevalence of proximal lesions, DNA mismatch repair deficient tumors etc). Estrogen is a well-accepted chemopreventive agent against CRC. Moreover, our group has reported that women have altered susceptibility to both genetic and environmental CRC risk factors. The epidemiological data has some studies suggesting an improved chemopreventive response to NSAIDS although there are discordant reports in the literature. Thus, the issue of whether women are more sensitive to NSAID chemoprevention is unresolved with possibility that NSAID type, dose etc may play a role. We recently conducted a chemoprevention trial using the NSAID celecoxib in a well-validated model of intestinal tumorigenesis, the MIN mouse. We noted that in this model, females were more responsive to the chemopreventive effects of celecoxib. The chemopreventive response was found to have regional propensity with stronger efficacy in the proximal intestine. Furthermore, celecoxib treated female mice had higher levels of mucosal estrogen receptor-2 (ER2) levels. We hypothesize that in colorectal cancer, NSAIDS present an increased chemopreventive efficacy in females which may be secondary to modulation of estrogen receptor ER2 expression. PUBLIC HEALTH RELEVANCE: Colorectal cancer is one of the major public health issues in US with life time risk of being diagnosed with this cancer is about 6%. This cancer usually develops slowly (10- 15 years) through multiple genetic and phenotypic transitions from normal colonic mucosa to adenoma and then to carcinoma. This protracted progression provides ample time for interventions such as endoscopic screening and removing adenomatous polyps. This has been promising but only about half of the at-risk population (age >50) receive any sort of effective screening. This underscores the need for developing alternate cancer prevention strategies such as chemoprevention. Number of studies shows that nonsteroidal anti-inflammatory drugs (NSAIDS) exert chemopreventive benefits against CRC. However, the overall efficacy is relatively modest (30-50% risk reduction) and requires more than a decade to show significant benefits. In addition, the use of NSAIDS has been shown to be linked to severe side-effects including ulcers, GI bleeding, hemorrhagic strokes etc, thereby causing some uncertainty in its use for preventing CRC for average risk use. To improve the risk-benefit analysis, it is therefore critical to selectively target subjects that can efficiently respond to chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDS). It has recently been shown that women with CRC may respond to dietary nutrients or pharmacological agents differently than men as they may have differing pathologies, risk factors and hormone status. The epidemiological studies suggest an improved chemopreventive response in women to NSAIDS although there are discordant reports in the literature. Thus, the issue of whether women are more sensitive to NSAID chemoprevention is unresolved with possibility that NSAIDS type, dose etc may play a role. The proposed studies will address the role of estrogen in gender selective chemopreventive efficacy of NSAIDS. These findings will have an important bearing on the healthcare recommendations for colon cancer chemoprevention which have to be cognizant of this gender selective efficacy for maximum cost-benefit potential of NSAIDS.